Alogliptina retarda a cicatrização de úlceras traumáticas orais em mucosa jugal de ratos wistar

Abstract

The healing of oral ulcers is a complex process and factors such as microbial infection can significantly interfere. Alogliptin is an oral hypoglycemic agent used in the treatment of type 2 diabetes mellitus, but this drug inhibits the activation of pathways of an important innate immune response receptor, the Toll-Like Receptor 4 (TLR4), which is fundamental in the recognition of gram-negative bacteria. The objective of this study was to evaluate the influence of Alogliptin treatment on the healing process of traumatic oral ulcers in the buccal mucosa of Wistar rats. Four experimental groups were used: control group (CG) treated with saline solution 0.1ml/kg/day and three test groups treated with Alogliptin 1 (GTA1), 3 (GTA3) and 9mg/kg/day (GTA9) orally. The ulcer was induced using a dermatological punch and the animals were euthanized on days 1, 3, 7 and 14 post ulceration. On these days, the ulcer diameter, weight variation and glycemic index were measured and superficial ulcer swab was collected for plating and colony forming units (CFU) count. In addition, an evaluation of Grimace scores was performed to analyze discomfort throughout this period. Slides stained with Hematoxylin & Eosin were prepared for microscopic analysis (healing scores) and histomorphometric (counting of polymorphonuclear and mononuclear inflammatory cells), as well as slides stained with Masson's Trichrome and Picrosirius Red for histochemical analysis (collagen deposition) and immunological analysis. -histochemistry for TLR4, TLR2,

Transforming Growth Factor (TGF)-β and CD31. ANOVA-2-way/Bonferroni and Kruskal- Wallis/Dunn tests were used for statistical analysis (GraphPad Prism 5.0®, p<0.05). Alogliptin

treatment increased the area (p<0.001) and the amount of CFU on the ulcer surface (p=0.049), while reducing the animals' body mass gain (p=0.007) in the GTA3 and GTA9 groups. There was an increase in Grimace scores and global discomfort throughout the evaluation period in the groups treated with the highest Alogliptin doses (p=0.02). In the microscopic analysis, an increase in histological scores (p=0.039) and in mononuclear cells (p=0.006) was observed, in addition to a reduction in the polymorphonuclear count (p<0.05) and in collagen deposition (p=0.031) in the GTA9 group. In addition, lower expression of TLR4 (p=0.001) and TGF-β (p<0.001) were observed, in addition to increased immunoexpression for CD31 (p<0.001) in the groups in the higher dose groups, as well as lower expression of TLR2 (p=0.001) in the higher dose group. It is concluded that treatment with Alogliptin is associated with delayed healing of oral ulcers, probably due to lower expression of TLR4 and TLR2 receptors and, consequently, increased microbiological density on the ulcer surface. Impairment of the healing process was observed, with permanence of the inflammatory process and decreased expression of TGF-β associated with less collagen deposition.